In addition to endothelial cells and vascular smooth muscle cells, we demonstrated that adrenomedullin (AM) is synthesized and secreted from fibroblasts, Swiss 3T3, Hs68, and NHLF cells, in a native and biologically active form. Synthesis and secretion of AM from these fibroblasts was regulated by inflammatory cytokines, such as tumor necrosis factor and interleukin-1, lipopolysaccharide, growth and differentiation factors, and hormones in a manner similar to that of vascular smooth muscle cells and endothelial cells. Tumor necrosis factor-α, interleukin-1β, and dexamethasone elevated AM secretion, whereas transforming growth factor-β1 and interferon-γ suppressed it in these three fibroblasts. Swiss 3T3 cells were shown to express receptors specific for AM by both cAMP production and receptor binding assay, and AM was found to stimulate DNA synthesis of quiescent cells through the cAMP-mediated pathway. AM secreted from Swiss 3T3 cells was also confirmed to augment cAMP production and DNA synthesis in the cells themselves. These effects were inhibited by a neutralizing monoclonal antibody against AM. These findings raise the possibility that AM functions as a growth regulator in the case of Swiss 3T3 cells. As AM receptors are widely distributed, AM secreted from fibroblast may play a role as a local regulator in mesenchymal cells of inflammatory or wounded regions.
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